Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes
Authors: Catherine Schramm, Camille Charbonnier, Aline Zaréa, Morgane Lacour, David Wallon, Daniela Andriuta, Pierre Anthony, Sophie Auriacombe, Anna-Chloé Balageas, Guillaume Ballan, Mélanie Barbay, Emilie Beaufils, Yannick Béjot, Serge Belliard, Marie Benaiteau, Karim Bennys, Frédéric Blanc, Stéphanie Bombois, Claire Boutoleau Bretonnière, Pierre Branger, Jasmine Carlier, Leslie Cartz-Piver, Pascaline Cassagnaud, Giovanni Castelnovo, Christine Champion, Annabelle Chaussenot, Mathieu Ceccaldi, Valérie Chauviré, Yaohua Chen, Julien Cogez, Emmanuel Cognat, Fabienne Contegal-Callier, Lea Corneille, Philippe Couratier, Hélène Courtemanche, Benjamin Cretin, Charlotte Crinquette, Bernard Croisille, Benjamin Dauriat, Sophie Dautricourt, Vincent de la Sayette, Astrid De liège, Marie De Verdal, Didier Deffond, Benoit Delpont, Florence Demurger, Vincent Deramecourt, Céline Derollez, Mira Didic, Giulia Diemert, Elsa Dionet, Philippe Diraison, Aude Doan, Martine Doco Fenzy, Boris Dufournet, Julien Dumurgier, Hélène Durand, Anaïs Dutray, Frédérique Etcharry-Bouyx, Maïté Formaglio, Audrey Gabelle, Anne Gainche-Salmon, Jean-Claude Getenet, Emmanuelle Ginglinger, Olivier Godefroy, Mathilde Graber, Chloé Gregoire, Stephan Grimaldi, Julien Gueniat, Claude Gueriot, Sophie Haffen, Lorraine Hamelin, Didier Hannequin, Cezara Hanta, Clémence Hardy, Geoffroy Hautecloque, Camille Heitz, Claire Hourregue, Thérèse Jonveaux, Snejana Jurici, Catia Khoumri, Lejla Koric, Pierre Krolak-Salmon, Pierre Labauge, Morgane Lacour, Julien Lagarde, Hélène-Marie Lanoiselée, Brice Laurens, Isabelle Le Ber, Gwenaël Le Guyader, Amélie Leblanc, Thibaud Lebouvier, Anaïs Lippi, Marie-Anne Mackowiak, Eloi Magnin, Cecilia Marelli, Olivier Martinaud, Aurélien Maureille, Emilie Milongo-Rigal, Sophie Mohr, Hélène Mollion, Olivier Moreaud, Alexandre Morin, Gaël Nicolas, Julia Nivelle, Camille Noiray, Elisabeth Ollagnon-Roman, Claire Paquet, Jérémie Pariente, Florence Pasquier, Alexandre Perron, Nathalie Philippi, Virginie Pichon, Vincent Planche, Céline Poirsier, Marie Rafiq, Pauline Rod-Olivieri, Adeline Rollin-Sillaire, Carole Roué-Jagot, Dario Saracino, Marie Sarazin, Mathilde Sauvée, François Sellal, Lila Sirven Villaros, Christel Thauvin, Camille Tisserand, Christophe Tomasino, Cédric Turpinat, Laurène Van Damme, Olivier Vercruysse, Alice Voilly, Nathalie Wagemann, David Wallon, Aline Zarea, Anne Boland, Jean-François Deleuze, Robert Olaso, Shahzad Ahmad, Philippe Amouyel, Claudine Berr, Anne Boland, Paola Bossu, Femke Bouwman, Jose Bras, Dominique Campion, Camille Charbonnier, Jordi Clarimon, Antonio Daniele, Jean-François Dartigues, Stéphanie Debette, Jean-François Deleuze, Nicola Denning, Oriol Dols-Icardo, Nick C. Fox, Daniela Galimberti, Emmanuelle Génin, Hans Gille, Benjamin Grenier-Boley, Detelina Grozeva, Rita Guerreiro, John J. Hardy, Clive Holmes, Henne Holstege, Marc Hulsman, Holger Hummerich, M. Arfan Ikram, M. Kamran Ikram, Iris Jansen, Amit Kawalia, Robert Kraaij, Jean-Charles Lambert, Marc Lathrop, Afina W. Lemstra, Alberto Lleo, Lauren Luckcuck, Marcel M. A. M. Mannens, Rachel Marshall, Carlo Masullo, Simon Mead, Patrizia Mecocci, Alun Meggy, Merel O. Mol, Kevin Morgan, Benedetta Nacmias, Gaël Nicolas, Penny J. Norsworthy, Florence Pasquier, Pau Pastor, Olivier Quenez, Alfredo Ramirez, Rachel Raybould, Richard Redon, Marcel J. T. Reinders, Anne-Claire Richard, Steffi G. Riedel-Heller, Fernando Rivadeneira, Stéphane Rousseau, Natalie S. Ryan, Salha Saad, Pascual Sanchez-Juan, Philip Scheltens, Jonathan M. Schott, Davide Seripa, Daoud Sie, Rebecca Sims, Erik Sistermans, Sandro Sorbi, Resie van Spaendonk, Gianfranco Spalleta, Nicćolo Tesi, Betty Tijms, André G. Uitterlinden, Wiesje M. van der Flier, Sven J. van der Lee, Cornelia M. van Duijn, Jeroen G. J. van Rooij, John C. van Swieten, Pieter J. de Visser, Michael Wagner, David Wallon, Julie Williams, Aline Zarea, Flora Alarcon, Dominique Campion, Grégory Nuel, Gaël Nicolas
Journal: Genome Medicine (2022)

Abstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications.